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dc.contributor.advisorGani, D. (David)
dc.contributor.authorHawkins, Paul Charles David
dc.coverage.spatial263 p.en_US
dc.description.abstractA series of experiments, designed to investigate two mutually incompatible theories of the catalysis carried out by pepsin, the archetypal aspartic protease, were undertaken. Mechanism-activated active-site probes, based on acyl hydrazides, were synthesised, but could not be shown to inactivate pepsin. Experiments designed to trap a covalent intermediate in pepsin catalysis were also carried out, but did not provide any evidence for such an intermediate. A number of methyl hydrogen 1-aminoalkyl phosphonates have been synthesised. They were used, by co-workers in the group, in the synthesis of phosphonamidate-containing penta- and hexapeptide-based inhibitors for the aspartic protease from HIV-1. These compounds were found to be inhibitors in both in vitro and in vivo assays. The best inhibitors had IC50 values in the low micromolar range. Molecular modelling was used to develop a model for the interaction of these compounds with the active site of the protease. This model was used to rationalise some of the results obtained from the inhibitors. Attempts were made to clone, overexpress and purify the protease from E. coli. The protease was purified to homogeneity but no activity could be observed. Various attempts to obtain activity were unsuccessful.en_US
dc.publisherUniversity of St Andrews
dc.titleStereochemical and mechanistic studies on the aspartic proteasesen_US
dc.contributor.sponsorBiotechnology and Biological Sciences Research Council (BBSRC)en_US
dc.type.qualificationnamePhD Doctor of Philosophyen_US
dc.publisher.institutionThe University of St Andrewsen_US

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